"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
About one fourth of patients with muscle-invasive bladder cancer (MIBC) have lymph node metastases. The gold standard for management of MIBC has been radical removal of the bladder with concomitant pelvic lymph node dissection (LND) -- i.e., radical cystectomy. This also provides prognostic information about locally advanced disease, with the potential to help prevent the cancer from spreading.
National and international guidelines for MIBC support the role of lymph node removal during radical cystectomy. The standard bilateral pelvic lymphadenectomy template includes the external and internal iliac and obturator nodes, with removal of a minimum of 12 lymph nodes.
Survival outcomes are superior with any LND compared with no LND, but early studies were performed without neoadjuvant chemotherapy (NAC). Although NAC followed by radical cystectomy is the standard treatment for cT2–4aN0M0 bladder cancer, clear evidence of any survival benefit for LND after NAC is lacking.
The optimal specifics for LND have been controversial, but recent data do offer some clarity about the appropriate extent of the dissection.
"The limited template for pelvic LND includes perivascular nodes and lymphatic tissue in the obturator fossa, limited laterally by the external iliac vein and medially by the obturator nerve," researchers wrote in a 2014 review. A larger limited (also called "standard") lymphadenectomy template "is bounded distally by the circumflex iliac vein and Cloquet's node, laterally by the genitofemoral nerve, medially by the bladder and internal iliac vessels, posteriorly by the obturator fossa, and proximally by the bifurcation of (or distal aspect of) the common iliac artery."
An extended template for lymphadenectomy includes the presacral and common iliac lymph nodes up to the aortic bifurcation. Removal of the retroperitoneal lymph node proximal to the aortic bifurcation to the level of the inferior mesenteric artery is referred to as a superextended lymph node dissection.
While an extended pelvic LND can potentially eradicate micrometastatic disease and improve pathologic staging, similar to the situation with LND after NAC, neither an extended nor a superextended template has proven to have a survival benefit.
"Depending on where you train, the thinking is that you should go super high with your lymph node dissection," said Joshua Meeks, MD, PhD, of Northwestern Medicine in Chicago. "It's very similar to the old Halstedian concept of the more nodes the better."
Eugene Pietzak, MD, of Memorial Sloan Kettering Cancer Center in New York City, said, "Surgeons like to think that doing more [extensive LND] is beneficial for the patient, but they don't necessarily know that. It's almost like surgical dogma to a certain extent."
He pointed to a prospective randomized German study that showed trends toward superior recurrence-free survival (RFS), cancer-specific survival, and OS with an extended LND versus a more limited dissection in patients with bladder cancer undergoing radical cystectomy. The study, though, did not meet its primary outcome, possibly because it was underpowered to detect the prespecified 15% effect size for RFS in favor of extended LND. "In order to demonstrate a 5% effect size, you would probably need more than 1,000 patients to be randomized," he said.
In the study, 5-year RFS was 65% in the extended LND arm vs 59% in the limited dissection arm (HR 0.84, 95% CI 0.58-1.22, P=0.36). The 5-year cancer-specific survival rate was 76% vs 65%, respectively (HR 0.70, P=0.10), and 5-year OS rate was 59% vs 50%, respectively (HR 0.78, P=0.12). The authors hypothesized that inclusion of T1G3 tumors may have contributed to the negative result, and that a larger trial would be required to determine whether extended compared with limited LND would lead to a small survival difference.
Enter SWOG S1011 and a New Standard
"Extended lymphadenectomy is considered a standard of care and is increasingly used, especially for patients with locally advanced bladder cancer, who have a higher risk of lymph node metastases," said Seth Lerner, MD, of Baylor College of Medicine in Houston.
This standard was challenged in the phase III SWOG S1011 study, in which 618 patients with histologically confirmed cT2-4a N0-2 urothelial cancer undergoing radical cystectomy were randomized 1:1 to have either extended or standard LND, with the primary endpoint of disease-free survival (DFS). The 36 surgeons (from 27 sites in the U.S. and Canada) who performed the lymphadenectomies were credentialed prior to enrollment of patients. Those patients treated with NAC were required to complete it 70 days prior to registration; those who did not receive NAC had to undergo cystectomy within 4 weeks of registration. DFS was defined as first documentation of relapse or recurrence or death due to any cause.
Median follow-up was 6.1 years. The median number of nodes removed was greater in the patients randomized to extended LND 39 nodes vs 24 nodes in the control arm, but the percentage of nodes found to contain metastatic disease was similar between the two arms (26% vs 24%, respectively).
The 5-year DFS estimate was 58% in the standard lymphadenectomy arm vs 55% for extended LND (HR 1.10, 95% CI 0.87-1.42), and the OS rates were 63% and 59% (HR 1.15, 95% CI 0.89-1.48), respectively.
Patients in the extended LND arm were more likely to have grade 3 or 4 adverse events within 90 days of surgery than those who received a standard LND (49% vs 42%). Additionally, 19 patients in the extended LND arm died within 90 days of surgery compared with seven in the standard LND arm.
The findings are consistent with those from the LEA trial, which found that extended LND was not superior on the endpoints of RFS and OS in non-muscle-invasive bladder cancer, leading Lerner to conclude that "bilateral standard dissection confined to the true pelvis is the standard of care for patients with curable MIBC."
Trinity Bivalacqua, MD, PhD, director of Urologic Oncology at Penn Medicine in Philadelphia and one of the surgeons on the SWOG S1011 trial, said: "we are able to increase nodal yield and median number of lymph nodes that are positive. However there was no benefit ... there was greater perioperative morbidity related to thromboembolic events, and the mortality was increased in those patients with extended lymphadenectomy. I would say this is definitely practice changing."
Read previous installments in this series:
Part 1: Urothelial Cancer: Diagnostic Evaluation
Part 2: Staging of Urothelial Cancer: Cystoscopy and CT Evaluation Remain Standard
Part 3: Non-Muscle-Invasive Bladder Cancer: Intravesical BCG and Beyond
Part 4: Case Study: Recurrence of Urothelial Cancer Challenging in Patient With Morbid Obesity
Part 5: The Expanding Role of Immunotherapy for Muscle-Invasive Bladder Cancer